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PubMed2002

Rapid spread of a neurovirulent strain of HSV-1 through the CNS of BALB/c mice following anterior chamber inoculation.

Following uniocular anterior chamber (AC) inoculation of BALB/c mice with the KOS strain of herpes simplex virus type 1 (HSV-1), virus spreads from the injected eye to the ipsilateral suprachiasmatic nucleus (SCN) in the central nervous system (CNS) to infect the optic nerve and retina of the contralateral eye, and mice develop retinitis in that eye only. In contrast, after AC inoculation of BALB/c mice with the H129 strain of HSV-1, mice develop bilateral retinitis. The pathway(s) by which H129 spreads to cause bilateral retinitis is not known. To determine the route and timing of H129 spread after AC inoculation, BALB/c mice were injected in the AC of the right eye with 5 x 10(3) PFU of H129. Brains from 30 mice were sectioned on a brain matrix and the amount of virus in the brain and eyes was determined by plaque assay. Frozen sections were prepared from the eyes, brain, and trigeminal ganglia of an additional 30 mice, and HSV-1 antigen was detected by immunohistochemistry. After AC inoculation, H129 follows a pathway similar to KOS in the CNS, but H129 appears to spread more rapidly than KOS within the CNS. Unlike KOS, H129 is able to infect brain stem nuclei and H129-infected mice developed neurological impairments in addition to bilateral retinitis. The results of these studies suggest that the ability of H129 to spread rapidly in the CNS allows early virus infection of retino-recipient nuclei proximal to the contralateral and ipsilateral optic nerves. Early infection of retino-recipient nuclei, such as the SCN may allow virus to spread into the retinas before a virus-specific immune response can be induced.

Animals↗
PubMed1986

Variants of BALB/c 3T3 cells lacking complex gangliosides retain a fibronectin matrix and spread normally on fibronectin-coated substrates.

Evidence has accumulated that di- and trisialogangliosides are involved in the interaction of cells with fibronectin. We have therefore tested the ability of variants of BALB/c 3T3 deficient in such gangliosides to organize a fibronectin matrix and to spread on fibronectin-coated substrates. Whereas BALB/c 3T3 cells contained gangliosides GM3, GM1, and GD1a, direct chemical analysis showed that five out of six variants isolated contained no detectable GD1a. By the overlaying of thin layer chromatograms of cellular gangliosides with 125I-cholera toxin, these variants were also found to lack ganglioside GM1. In contrast, the sialogalactoprotein profile of these cells, analyzed using an 125I-ricin/SDS polyacrylamide gel overlay technique, was similar to that of the parent cell line. All variants organized an extensive fibronectin matrix comparable to that of BALB/c 3T3, as shown using either immunofluorescence or lactoperoxidase-catalyzed iodination. The variants could also spread on fibronectin-coated substrates and adopt a morphology similar to that of BALB/c 3T3 cells, with little or no difference in the concentration of fibronectin required for 50% cell spreading. Cell spreading of the variants was accompanied by the formation of focal contacts and microfilament bundles, in a manner closely resembling that seen with BALB/c 3T3 cells. Treatment of BALB/c 3T3 cells with neuraminidase, which converts much of the cellular GD1a to GM1, did not affect cell spreading on fibronectin. The results clearly demonstrate that complex gangliosides are not essential for retention of a fibronectin matrix or for spreading on fibronectin-coated substrates.

Actin Cytoskeleton↗
PubMed1987

Fibrinogen induces adhesion, spreading, and microfilament organization of human endothelial cells in vitro.

Human umbilical vein endothelial cells (ECs) have been shown to attach to a substratum of fibrinogen (fg). Later, ECs undergo spreading, organization of thick microfilament bundles of the stress fiber type, and formation of focal contacts (adhesion plaques) that correspond to accumulation of vinculin at the cytoplasmic aspect of the ventral membrane. The rate of attachment to fg and the type of spreading is virtually identical to that obtained on substrata coated with fibronectin (FN). Antibodies to fg, but not to FN, prevent EC adhesion to fg; conversely, antibodies to FN, but not to fg, prevent adhesion of ECs to a FN-coated substratum. The removal of residual FN contamination from fg preparations by means of DEAE-cellulose chromatography does not result in any difference in EC adhesion on fg. Moreover, pretreatment of cells with inhibitors of synthesis and release of proteins does not impair their adhesion capacity on an fg-coated substratum. In contrast, human arterial smooth muscle cells do not adhere and spread on fg substrata but do so on FN. The synthetic peptides (Gly-Arg-Gly-Asp[GRGD] and Gly-Arg-Gly-Asp-Ser-Pro[GRGDSP]) containing the tripeptide Arg-Gly-Asp (RGD), originally found to be responsible for the cell binding activity of FN, have been found to inhibit EC spreading and the redistribution of their cytoskeleton, including the formation of stress fibers and the localization of vinculin either on fg or on FN. Conversely, the synthetic peptide Arg-Gly-Gly (RGG) was completely uneffective in inhibiting the adhesion and the sequence of events leading to spreading and cytoskeletal organization. These results indicate that ECs, but not smooth muscle cells, specifically adhere and spread on an fg substratum and this occurs by recognition mechanisms similar to those reported for FN.

Actin Cytoskeleton↗
PubMed1990

Characterization of a synthetic peptide from type IV collagen that promotes melanoma cell adhesion, spreading, and motility.

The adhesion and motility of tumor cells on basement membranes is a central consideration in tumor cell invasion and metastasis. Basement membrane type IV collagen directly promotes the adhesion and migration of various tumor cell types in vitro. Our previous studies demonstrated that tumor cells adhered and spread on surfaces coated with intact type IV collagen or either of the two major enzymatically purified domains of this protein. Only one of these major domains, the pepsin-generated major triple helical fragment, also supported tumor cell motility in vitro, implicating the involvement of the major triple helical region in type IV collagen-mediated tumor cell invasion in vivo. The present studies extend our previous observations using a synthetic peptide approach. A peptide, designated IV-H1, was derived from a continuous collagenous region of the major triple helical domain of the human alpha 1(IV) chain. This peptide, which has the sequence GVKGDKGNPGWPGAP, directly supported the adhesion, spreading, and motility of the highly metastatic K1735 M4 murine melanoma cell line, as well as the adhesion and spreading of other cell types, in a concentration-dependent manner in vitro. Furthermore, excess soluble peptide IV-H1, or polyclonal antibodies directed against peptide IV-H1, inhibited type IV collagen-mediated melanoma cell adhesion, spreading, and motility, but had no effect on these cellular responses to type I collagen. The full complement of cell adhesion, spreading, and motility promoting activities was dependent upon the preservation of the three prolyl residues in the peptide IV-H1 sequence. These studies indicate that peptide IV-H1 represents a cell-specific adhesion, spreading, and motility promoting domain that is active within the type IV collagen molecule.

Amino Acid Sequence↗
PubMed1993

Distinct functions of integrin alpha and beta subunit cytoplasmic domains in cell spreading and formation of focal adhesions.

Integrin-mediated cell adhesion often results in cell spreading and the formation of focal adhesions. We exploited the capacity of recombinant human alpha IIb beta 3 integrin to endow heterologous cells with the ability to adhere and spread on fibrinogen to study the role of integrin cytoplasmic domains in initiation of cell spreading and focal adhesions. The same constructs were also used to analyze the role of the cytoplasmic domains in maintenance of the fidelity of the integrin repertoire at focal adhesions. Truncation mutants of the cytoplasmic domain of alpha IIb did not interfere with the ability of alpha IIb beta 3 to initiate cell spreading and form focal adhesions. Nevertheless, deletion of the alpha IIb cytoplasmic domain allowed indiscriminate recruitment of alpha IIb beta 3 to focal adhesions formed by other integrins. Truncation of the beta 3 subunit cytoplasmic domain abolished cell spreading mediated by alpha IIb beta 3 and also abrogated recruitment of alpha IIb beta 3 to focal adhesions. This truncation also dramatically impaired the ability of alpha IIb beta 3 to mediate the contraction of fibrin gels. In contrast, the beta 3 subunit cytoplasmic truncation did not reduce the fibrinogen binding affinity of alpha IIb beta 3. Thus, the integrin beta 3 subunit cytoplasmic domain is necessary and sufficient for initiation of cell spreading and focal adhesion formation. Further, the beta 3 cytoplasmic domain is required for the transmission of intracellular contractile forces to fibrin gels. The alpha subunit cytoplasmic domain maintains the fidelity of recruitment of the integrins to focal adhesions and thus regulates their repertoire of integrins.

Amino Acid Sequence↗
PubMed1998

Calpain regulates actin remodeling during cell spreading.

Previous studies suggest that the Ca2+-dependent proteases, calpains, participate in remodeling of the actin cytoskeleton during wound healing and are active during cell migration. To directly test the role that calpains play in cell spreading, several NIH-3T3- derived clonal cell lines were isolated that overexpress the biological inhibitor of calpains, calpastatin. These cells stably overexpress calpastatin two- to eightfold relative to controls and differ from both parental and control cell lines in morphology, spreading, cytoskeletal structure, and biochemical characteristics. Morphologic characteristics of the mutant cells include failure to extend lamellipodia, as well as abnormal filopodia, extensions, and retractions. Whereas wild-type cells extend lamellae within 30 min after plating, all of the calpastatin-overexpressing cell lines fail to spread and assemble actin-rich processes. The cells genetically altered to overexpress calpastatin display decreased calpain activity as measured in situ or in vitro. The ERM protein ezrin, but not radixin or moesin, is markedly increased due to calpain inhibition. To confirm that inhibition of calpain activity is related to the defect in spreading, pharmacological inhibitors of calpain were also analyzed. The cell permeant inhibitors calpeptin and MDL 28, 170 cause immediate inhibition of spreading. Failure of the intimately related processes of filopodia formation and lamellar extension indicate that calpain is intimately involved in actin remodeling and cell spreading.

3T3 Cells↗
PubMed1980

Antisera inhibiting mammalian cell spreading and possible cell surface antigens involved.

Antiserum against a rat neuronal tumor cell line (B103) has been prepared in rabbit by intravenous injection of live cells. This immune serum (anti-B103) precipitates a few cell surface proteins recognizable by two-dimensional gel electrophoresis as common radioiodinatable spots in 15 different rat neural cell lines and in mouse and rat fibroblast cell lines. The apparent molecular weight of one major common protein (II4) is estimated by SDS gel electrophoresis to be somewhere between 80,000 and 90,000 and another protein (I3) to be 120,000. These two proteins are consistently recognized in various cell lines by this antiserum. Furthermore, at a 1:20 dilution, this serum causes monolayer cells to round up usually within 0.5 h and detach from the plate within 3 h. It also inhibits spreading of freshly plated cells. These effects of the antiserum are reversible. Upon absorption of the antiserum with cells (e.g., absorbed with a glial cell line, B27), the serum no longer causes the rounding up of the monolayer cells, it does not inhibit cell spreading, and it does not immune-precipitate the two common proteins from the cell surface of various cell lines. Antisera against several other rat cell lines also precipitate the same common proteins (II4 and I3) from the cell surface and prevent cell spreading. These data suggest that the antibody acts first at the cell surface and then inhibits cell spreading or rounding up of spread cells. The consistent pattern of the immunoprecipitated cell surface proteins on the two-dimensional gel electrophoresis makes these two common surface proteins (II4 or I3 or both) possible candidates for target proteins to which the antibody binds. Thus, they may play a critical role in cell spreading.

Animals↗
PubMed1979

The induction of macrophage spreading by factor B of the properdin system.

Unstimulated mouse peritoneal macrophages attached to a glass substratum responded to activated human factor B (Bb) of the properdin system but not to native factor B with rapid spreading and a concomitant increase in their apparent surface area. Excellent correlation of the distribution of Bb protein and cell-spreading activity was found upon purification of Bb by ion-exchange and molecular seive chromatography and alkaline polyacrylamide gel electrophoresis. 1.6 microgram of purified Bb was sufficient to induce spreading in 50% of 5 x 10(4) glass attached macrophages within 1-2 h at 37 degrees C. Treatment of Bb with di-isopropyl-fluorophosphate indicated that the intact catalytic site of the serine-proteinase Bb was required for the initiation of macrophage spreading. The involvement of factor B in the induction of rapid cell spreading could also be indirectly demonstrated in an autologous system in which F(ab')2 fragments of an antiserum to mouse B prevented mouse macrophages from spreading in response to complement-activated mouse serum. These experiments suggest a role for factor B and the alternative pathway of complement fixation in the localization of mononuclear phagocytes to areas of inflammation.

Animals↗
PubMed1996

A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease.

The development of autoimmune disease is accompanied by the acquired recognition of new self-determinants, a process commonly referred to as determinant spreading. In this study, we addressed the question of whether determinant spreading is pathogenic for progression of chronic-relapsing experimental autoimmune encephalomyelitis (EAE), a disease with many similarities to multiple sclerosis (MS). Our approach involved a systematic epitope mapping of responses to myelin proteolipid protein (PLP) as well as assaying responses to known encephalitogenic determinants of myelin basic protein (MBP 87-89) and myelin oligodendrocyte glycoprotein (MOG 92-106) at various times after induction of EAE in (SWR X SJL)F1 mice immunized with PLP 139-151. We found that the order in which new determinants are recognized during the course of disease follows a predictable sequential pattern. At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined. Three lines of evidence showed that determinant spreading is pathogenic for disease progression: (a) spreading determinants mediate passive transfer of acute EAE in naive (SWR X SJL)F1 recipients; (b) an invariant relationship exists between the development of relapse/progression and the spreading of recognition to new immunodominant encephalitogenic determinants; and (c) after EAE onset, the induction of peptide-specific tolerance to spreading but not to nonspreading encephalitogenic determinants prevents subsequent progression of EAE. Thus, the predictability of acquired self-determinant recognition provides a basis for sequential determinant-specific therapeutic intervention after onset of the autoimmune disease process.

Amino Acid Sequence↗
PubMed2001

The cytoplasmic domain of the integrin alpha9 subunit requires the adaptor protein paxillin to inhibit cell spreading but promotes cell migration in a paxillin-independent manner.

The integrin alpha9 subunit forms a single heterodimer, alpha9beta1. The alpha9 subunit is most closely related to the alpha4 subunit, and like alpha4 integrins, alpha9beta1 plays an important role in leukocyte migration. The alpha4 cytoplasmic domain preferentially enhances cell migration and inhibits cell spreading, effects that depend on interaction with the adaptor protein, paxillin. To determine whether the alpha9 cytoplasmic domain has similar effects, a series of chimeric and deleted alpha9 constructs were expressed in Chinese hamster ovary cells and tested for their effects on migration and spreading on an alpha9beta1-specific ligand. Like alpha4, the alpha9 cytoplasmic domain enhanced cell migration and inhibited cell spreading. Paxillin also specifically bound the alpha9 cytoplasmic domain and to a similar level as alpha4. In paxillin(-/-) cells, alpha9 failed to inhibit cell spreading as expected but surprisingly still enhanced cell migration. Further, mutations that abolished the alpha9-paxillin interaction prevented alpha9 from inhibiting cell spreading but had no effect on alpha9-dependent cell migration. These findings suggest that the mechanisms by which the cytoplasmic domains of integrin alpha subunits enhance migration and inhibit cell spreading are distinct and that the alpha9 and alpha4 cytoplasmic domains, despite sequence and functional similarities, enhance cell migration by different intracellular signaling pathways.

Amino Acid Motifs↗
PubMed1999

The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts.

Expression of full-length p16(INK4a) blocks alphavbeta3 integrin-dependent cell spreading on vitronectin but not collagen IV. Similarly, G1-associated cell cycle kinases (CDK) inhibitory (CKI) synthetic peptides derived from p16(INK4a), p18(INK4c) and p21(Cip1/Waf1), which can be delivered directly into cells from the tissue culture medium, do not affect non-alphavbeta3-dependent spreading on collagen IV, laminin and fibronectin at concentrations that inhibit cell cycle progression in late G1. The alphavbeta3 heterodimer remains intact after CKI peptide treatment but is immediately dissociated from the focal adhesion contacts. Treatment with phorbol 12-myristate 13-acetate (PMA) allows alphavbeta3 to locate to the focal adhesion contacts and the cells to spread on vitronectin in the presence of CKI peptides. The cdk6 protein is found to suppress p16(INK4a)-mediated inhibition of spreading and is also shown to localize to the ruffling edge of spreading cells, indicating a function for cdk6 in controlling matrix-dependent cell spreading. These results demonstrate a novel G1 CDK-associated integrin regulatory pathway that acts upstream of alphavbeta3-dependent activation of PKC as well as a novel function for the p16(INK4a) tumour suppressor protein in regulating matrix-dependent cell migration.

Amino Acid Sequence↗
PubMed1999

Localization of single- and low-copy sequences on tomato synaptonemal complex spreads using fluorescence in situ hybridization (FISH).

Fluorescence in situ hybridization (FISH) is a powerful means by which single- and low-copy DNA sequences can be localized on chromosomes. Compared to the mitotic metaphase chromosomes that are normally used in FISH, synaptonemal complex (SC) spreads (hypotonically spread pachytene chromosomes) have several advantages. SC spreads (1) are comparatively free of debris that can interfere with probe penetration, (2) have relatively decondensed chromatin that is highly accessible to probes, and (3) are about ten times longer than their metaphase counterparts, which permits FISH mapping at higher resolution. To investigate the use of plant SC spreads as substrates for single-copy FISH, we probed spreads of tomato SCs with two single-copy sequences and one low-copy sequence (ca. 14 kb each) that are associated with restriction fragment length polymorphism (RFLP) markers on SC 11. Individual SCs were identified on the basis of relative length, arm ratio, and differential staining patterns after combined propidium iodide (PI) and 4', 6-diamidino-2-phenylindole (DAPI) staining. In this first report of single-copy FISH to SC spreads, the probe sequences were unambiguously mapped on the long arm of tomato SC 11. Coupled with data from earlier studies, we determined the distance in micrometers, the number of base pairs, and the rates of crossing over between these three FISH markers. We also observed that the order of two of the FISH markers is reversed in relation to their order on the molecular linkage map. SC-FISH mapping permits superimposition of markers from molecular linkage maps directly on pachytene chromosomes and thereby contributes to our understanding of the relationship between chromosome structure, gene activity, and recombination.

Chromatin↗
PubMed1999

Patterns of local horizontal spread of melanomas: consequences for surgery and histopathologic investigation.

Understanding local spreading patterns of melanomas is a precondition for the localized surgical treatment and histopathologic investigation. We used hematoxylin and eosin-stained paraffin sections for a two-phase, cellular and microscopic study of patterns of lateral spread in superficial spreading melanomas (SSMs), nodular melanomas (NMs), lentigo maligna melanomas (LMMs), and acral lentiginous melanomas (ALMs). Complete histologic examination of vertical excisional margins was carried out with paraffin sections 5 mm beyond the clinical tumor border of 1395 SSMs, 376 NMs, 179 LMMs, 46 ALMs, and 37 acrally located SSMs or NMs. Further sections of embedded material were analyzed when tumor-positive margins were found. In case of continuous tumor spread, reoperations were continued until the tissue was free of tumor cells. In case of noncontinuity, a final excision was made to a minimum safety margin of 10 to 20 mm. Concentrically consecutive, 5-microm thick hematoxylin and eosin-stained sections were taken from the outside of a 10-mm safety margin inward to the clinical borders of 34 SSMs, five NMs, 10 LMMs, and five ALMs. Noncontinuous subclinical spread was found in all SSMs and NMs in the form of few isolated cell nests at the epidermis-dermis junction. Ninety-two percent of these were located within 6 mm of the central tumor. All LMMs and ALMs showed a clearly demonstrable, uninterrupted spread into the periphery at the epidermis-dermis junction, too, usually in groups of outgrowths. The probability of finding these outgrowths 5 mm beyond the clinical tumor border was 54% in LMM and ALM. Complete histologic examination of vertical excisional margins (micrographic surgery) is therefore the therapy of choice only for LMM and ALM and is inefficient for SSM and NM.

Humans↗
PubMedDate not supplied

Small cell lung carcinoma: Eight types of extension and spread on computed tomography.

OBJECTIVE: The aim of this study was to classify the types of tumor extension and spread of small cell lung carcinoma (SCLC) and to recognize the unusual types of spread pattern of SCLC on computed tomography (CT) including multidetector row CT (MDCT) using contrast-enhanced material. MATERIALS AND METHODS: Sixty-eight cases (53 men and 15 women aged 54-83 years old) of pathologically proven SCLC were examined mainly by contrast-enhanced CT scan. In surgically treated 7 cases, CT-pathologic correlations were performed. RESULTS: Eight types of extension and spread were recognized by the examinations of chest CT. The type of central mass + mediastinal extension (n = 20 [29.4%]) was the most common manifestation. The types of central perihilar mass (n = 12 [17.6%]), peripheral mass + mediastinal extension (n = 14 [20.6%]), and peripheral mass (n = 7 [10.3%]) were frequently observed. The primary site of SCLC was in peripheral lung tissue in 21 of 68 cases (30.9%) in this study. Unusual CT manifestations, such as the types of lymphangitic spread (n = 6 [8.8%]), pleural dissemination (n = 4 [5.9%]), lobar replacement (n = 3 [4.4%]), pneumonialike air-space infiltrative spread (n = 2 [2.9%]) were recognized in our study. Stenosis of trachea and main bronchus caused by peribronchial extension were commonly noted. In the advanced cases with mediastinal extension, we observed the extension of SCLC to superior vena cava (n = 22), main pulmonary artery (n = 18), pulmonary vein (n = 11), and thoracic aortic wall (n = 7). Peri-and intracardial invasions were also observed in 9 cases. CONCLUSIONS: Computed tomography including MDCT analysis revealed 8 types of extension and spread of SCLC including unusual forms in 68 SCLC cases. Peribronchial extension and great vessel wall involvement, such as superior vena cava, main pulmonary artery, and peri-/intra-cardial extension, were commonly observed in advanced stage.

Aged↗
PubMed1997

Local spread of metastatic vertebral tumors. A histologic study.

STUDY DESIGN: Nineteen solitary metastatic vertebral tumors obtained by total en bloc spondylectomy were analyzed histologically. OBJECTIVES: To determine the mechanisms of local spread of vertebral tumors and identity barrier tissues to tumor progression in the vertebra. SUMMARY OF BACKGROUND DATA: Histologic studies of specimens resected at amputation or en bloc excision have determined the pattern of local spread of bone and soft tissue tumors in the extremities and identified barrier tissues to tumor spread. However, a similar assessment of vertebral malignancies is difficult. The development of total en bloc spondylectomy for primary vertebral malignancy and solitary has allowed the collection of tissue samples sufficient to analyze the pattern of local spread of tumors, using the concept of compartment and barrier. METHODS: Histologic sections of all vertebral elements were prepared from specimens collected after en bloc spondylectomy. Serial 5-mm sections in the sagittal plane were also prepared and examined. RESULTS: Analysis of tumor location showed that metastatic tumors reached the vertebral column by invading the bone marrow of the dorsal region of the vertebral body. The anterior longitudinal ligament, posterior longitudinal ligament, periosteum abutting the spinal canal, ligamentum flavum, periosteum of the lamina and spinous process, interspinous ligament, supraspinous ligament, cartilaginous endplate and the anulus fibrosus served as barriers to tumor progression. The posterior longitudinal ligament was the weakest barrier tissue and was gradually destroyed by the tumor at the point of perforating vessels. Even after destruction of the barrier tissue, tumor cells were covered with a thin, fibrous reactive membrane. Two pathways allowed tumor spread to the adjacent vertebrae: 1) from the edge of the vertebral body to the adjacent vertebral body beneath the longitudinal ligament, and 2) through the paravertebral muscles to the neighboring lamina. CONCLUSIONS: Each vertebra can be represented by a compartment surrounded by several barriers. The most common path for tumor spread is through the posterior longitudinal ligament to the epidural space.

Aged↗
PubMed2003

The management of perineural spread of squamous cell carcinoma to the ocular adnexae.

PURPOSE: To analyze a series of patients with periorbital perineural spread of squamous cell carcinoma and propose treatment guidelines. METHODS: Retrospective, noncomparative, interventional case series of 17 patients with clinical, radiologic, or histologic evidence of distant perineural spread. Treatment, recurrence, progression, and mortality rates were recorded. RESULTS: Numbness and pain were the most common symptoms, whereas ophthalmoplegia, ptosis, and facial palsy were the most frequent signs. All cases received wide-field radiotherapy to at least 50 Gy. Chemotherapy and surgery (biopsy, debulking, exenteration) were used in selected cases. Disease progression occurred in 6 patients, 4 of whom died. Median disease-free survival in the remainder was 37.5 months. CONCLUSIONS: The diagnosis of perineural spread is largely clinical and may be confirmed with imaging findings in the majority of cases. The role of biopsy is usually complementary but may be essential in some cases. In patients with evidence of distant perineural spread, radiotherapy volumes inclusive of potential antegrade and retrograde spread are recommended. Three-dimensional conformal planning or intensity-modulated radiation therapy assists in minimizing damage to adjacent structures. Synchronous chemotherapy should be considered to potentiate the effectiveness of radiation. The place of surgery in the treatment of perineural spread is palliative.

Adult↗
PubMed1979

The spread of a pathogenic and an apathogenic strain of Newcastle disease virus in the chick embryo as depending on the protease sensitivity of the virus glycoproteins.

The pathogenic strain Italien and the apathogenic strain Ulster of Newcastle disease virus have been compared with respect to organ tropism and spread of infection in 11-day-old chick embryos. After infection of the endodermal layer of the chorioallantoic membrane by intra-allantoic inoculation with strain Italien, high virus titres are found in all extra-embryonic membranes and fluids and in the embryo itself. Infection results in early death of the embryo. In contrast, after infection with strain Ulster by the same route of inoculation, high virus titres are found only in the allantoic sac and embryos are not killed. Inoculations with strain Italien on to the ectodermal layer through an artificial air sac results in rapid spread of infection in the chorioallantoic membrane and the embryo dies before the virus invades other tissues including the embryo. Under the same conditions of infection, strain Ulster neither spreads within chorioallantoic membrane nor does it kill the embryo. Virus spread in each germinal layer of the chorioallantoic membrane was analysed by immune fluorescence. These studies showed that endoderm as well as mesoderm and ectoderm allowed the spread of strain Italien, whereas only the endoderm is permissive for strain Ulster. These differences in host range are based upon differential activation of the virus glycoproteins by proteolytic cleavage. The glycoproteins of strain Italien are cleaved in each germinal layer, whereas those of strain Ulster are cleaved only in endoderm. These studies demonstrate that, in the system analysed here, spread of infection and organ tropism are important factors for pathogenicity and both of these factors are determined by the susceptibility of the virus glycoproteins to proteolytic cleavage.

Allantois↗
PubMed1994

Role of envelope glycoproteins gI, gp63 and gIII in the invasion and spread of Aujeszky's disease virus in the olfactory nervous pathway of the pig.

One-week-old pigs were infected intranasally with the Ka strain of Aujeszky's disease virus (ADV) or with mutants that were lacking the non-essential envelope glycoproteins gI, gp63 or gIII. The invasion and spread of these strains in the olfactory nervous pathway were examined by assessing virus levels and by localizing viral antigens in the olfactory mucosa representing the first neuronal level, in the olfactory bulb representing the second neuronal level and in the lateral olfactory gyrus, the rostral perforated substance and the piriform lobe, all representing the third neuronal level. The Ka parental strain invaded and spread up to the third neuronal level. The extent of invasion and spread of the gIII- mutant were similar to those of the parental strain. The gp63- mutant replicated normally in the olfactory mucosa, but its spread to all the other levels was limited as compared with that of the parental strain. The gI- mutant showed a defect in infection at all neuronal levels. These results indicate that, of the non-essential envelope glycoproteins, gI plays the major role in neural invasion and spread of ADV in its natural host. The pattern of invasion and spread of these mutants in the olfactory pathway of pigs was similar to that previously observed in the trigeminal pathway. The type of nervous pathway therefore appears not to influence the neuropathogenesis of ADV or mutants deleted in non-essential envelope glycoproteins in the pig.

Animals↗